PMID- 38317079 OWN - NLM STAT- MEDLINE DCOM- 20240207 LR - 20240210 IS - 1528-3658 (Electronic) IS - 1076-1551 (Print) IS - 1076-1551 (Linking) VI - 30 IP - 1 DP - 2024 Feb 5 TI - Platelet-derived growth factor signaling in pericytes promotes hypothalamic inflammation and obesity. PG - 21 LID - 10.1186/s10020-024-00793-z [doi] LID - 21 AB - BACKGROUND: Pericytes are a vital component of the blood-brain barrier, and their involvement in acute inflammation was recently suggested. However, it remains unclear whether pericytes contribute to hypothalamic chronic inflammation and energy metabolism in obesity. The present study investigated the impact of pericytes on the pathophysiology of obesity by focusing on platelet-derived growth factor (PDGF) signaling, which regulates pericyte functions. METHODS: Tamoxifen-inducible systemic conditional PDGF receptor beta knockout mice (Pdgfrb(∆SYS)-KO) and Calcium/calmodulin-dependent protein kinase type IIa (CaMKIIa)-positive neuron-specific PDGF receptor beta knockout mice (Pdgfrb(∆CaMKII)-KO) were fed a high-fat diet, and metabolic phenotypes before and 3 to 4 weeks after dietary loading were examined. Intracellular energy metabolism and relevant signal transduction in lipopolysaccharide- and/or platelet-derived growth factor-BB (PDGF-BB)-stimulated human brain pericytes (HBPCs) were assessed by the Seahorse XFe24 Analyzer and Western blotting. The pericyte secretome in conditioned medium from HBPCs was studied using cytokine array kit, and its impact on polarization was examined in bone marrow-derived macrophages (BMDMs), which are microglia-like cells. RESULTS: Energy consumption increased and body weight gain decreased after high-fat diet loading in Pdgfrb(∆SYS)-KO mice. Cellular oncogene fos (cFos) expression increased in proopiomelanocortin (POMC) neurons, whereas microglial numbers and inflammatory gene expression decreased in the hypothalamus of Pdgfrb(∆SYS)-KO mice. No significant changes were observed in Pdgfrb(∆CaMKII)-KO mice. In HBPCs, a co-stimulation with lipopolysaccharide and PDGF-BB shifted intracellular metabolism towards glycolysis, activated mitogen-activated protein kinase (MAPK), and modulated the secretome to the inflammatory phenotype. Consequently, the secretome showed an increase in various proinflammatory chemokines and growth factors including Epithelial-derived neutrophil-activating peptide 78 (C-X-C motif chemokine ligand (CXCL)5), Thymus and activation-regulated chemokine (C-C motif chemokine (CCL)17), Monocyte chemoattractant protein 1 (CCL2), and Growth-regulated oncogene alpha (CXCL1). Furthermore, conditioned medium from HBPCs stimulated the inflammatory priming of BMDMs, and this change was abolished by the C-X-C motif chemokine receptor (CXCR) inhibitor. Consistently, mRNA expression of CXCL5 was elevated by lipopolysaccharide and PDGF-BB treatment in HBPCs, and the expression was significantly lower in the hypothalamus of Pdgfrb(∆SYS)-KO mice than in control Pdgfrb(flox/flox) mice (FL) following 4 weeks of HFD feeding. CONCLUSIONS: PDGF receptor beta signaling in hypothalamic pericytes promotes polarization of macrophages by changing their secretome and contributes to the progression of obesity. CI - (c) 2024. The Author(s). FAU - Okekawa, Akira AU - Okekawa A AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. FAU - Wada, Tsutomu AU - Wada T AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. twada@pha.u-toyama.ac.jp. FAU - Onogi, Yasuhiro AU - Onogi Y AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. AD - Research Center for Pre-Disease Science, University of Toyama, 2630 Sugitani, Toyama, Japan. FAU - Takeda, Yuki AU - Takeda Y AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. FAU - Miyazawa, Yuichiro AU - Miyazawa Y AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. FAU - Sasahara, Masakiyo AU - Sasahara M AD - Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan. FAU - Tsuneki, Hiroshi AU - Tsuneki H AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. AD - Department of Integrative Pharmacology, University of Toyama, 2630 Sugitani, Toyama, Japan. FAU - Sasaoka, Toshiyasu AU - Sasaoka T AUID- ORCID: 0000-0003-3057-8674 AD - Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. tsasaoka@pha.u-toyama.ac.jp. LA - eng GR - JP21K08549/JSPS KAKENHI/ GR - 23H02957/JSPS KAKENHI/ GR - JPMJSP2145/JST SPRING/ GR - JPMJMS2021/JST Moonshot R&D/ PT - Journal Article DEP - 20240205 PL - England TA - Mol Med JT - Molecular medicine (Cambridge, Mass.) JID - 9501023 RN - 0 (Platelet-Derived Growth Factor) RN - 1B56C968OA (Becaplermin) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta) RN - 0 (Culture Media, Conditioned) RN - 0 (Lipopolysaccharides) RN - 0 (Proto-Oncogene Proteins c-sis) SB - IM MH - Mice MH - Humans MH - Animals MH - *Platelet-Derived Growth Factor/metabolism/pharmacology MH - *Pericytes/metabolism MH - Becaplermin/metabolism MH - Receptor, Platelet-Derived Growth Factor beta/genetics/metabolism MH - Culture Media, Conditioned/metabolism MH - Lipopolysaccharides MH - Signal Transduction MH - Inflammation/metabolism MH - Mice, Knockout MH - Obesity/metabolism MH - Hypothalamus MH - Proto-Oncogene Proteins c-sis/genetics/metabolism PMC - PMC10845801 OTO - NOTNLM OT - Inflammation OT - Microglia OT - Obesity OT - Pericytes OT - Platelet-derived growth factor COIS- The authors declare no competing interests. EDAT- 2024/02/06 00:42 MHDA- 2024/02/07 06:41 PMCR- 2024/02/05 CRDT- 2024/02/05 23:44 PHST- 2023/10/05 00:00 [received] PHST- 2024/01/25 00:00 [accepted] PHST- 2024/02/07 06:41 [medline] PHST- 2024/02/06 00:42 [pubmed] PHST- 2024/02/05 23:44 [entrez] PHST- 2024/02/05 00:00 [pmc-release] AID - 10.1186/s10020-024-00793-z [pii] AID - 793 [pii] AID - 10.1186/s10020-024-00793-z [doi] PST - epublish SO - Mol Med. 2024 Feb 5;30(1):21. doi: 10.1186/s10020-024-00793-z.